The rapid onset and persistence of homologous and heterologous protection induced by attenuated Venezuelan equine encephalomyelitis (VEE) vaccine (TC-83) were studied in the hamster, by using challenge response as the index of protection. At 8 hr postvaccination with 1,000 median immunizing doses of TC-83 vaccine, 15 to 20% of animals were protected against challenge with VEE virus as well as Eastern and Western equine encephalomyelitis viruses. The percentage of protection increased with time postvaccination until 80 to 90% homologous and heterologous protection was achieved by 18 hr postvaccination. Temporal studies indicated that early protection (days 1 to 6) correlated with vaccine viremia, and that the percentage of protection against heterologous challenge decreased with the cessation of viremia. Data are presented to indicate that the early protection phenomenon is one of interference, since little or no replication of a challenge virus occurred when it was administered during the vaccine viremia stage.